Our objective is to determine the extent to which different aspects of conditioned fear are relevant to features of particular forms of normal and abnormal anxiety in humans. We make a distinction between two forms of aversive states, fear and anxiety, with a particular focus on anxiety. Operationally, fear is defined as a phasic aversive state induced by a proximal and identifiable threat, whereas anxiety is a more sustained form of response focused on potential distal or future threats that are not clearly identifiable. Research in animals suggests that these two forms of aversive states can be modeled by cue and context conditioning, respectively.[unreadable] [unreadable] Experimental models: We focus on developing models of anxiety based on their presumed clinical relevance. In the last several years, we used virtual reality to model cue and context conditioning. In this experiment, fear and anxiety are assessed based on physiological responses. We recently introduced a new experiment, a virtual reality analogue of the Morris water maze. In this task, anxiety is measured based on behavior. The Morris water task also presents important procedural differences compared to context conditioning. The shock is uncontrollable in context conditioning, whereas stressor duration is contingent on subjects behavior (i.e., reaching the hidden platform) in the Morris water maze. [unreadable] [unreadable] Psychopharmacology: We have demonstrated that contextual anxiety is increased by acute citalopram and reduced by 2-week treatment with the serotoninergic reuptake inhibitor (SSRI), citalopram. These results are consistent with the effects of SSRI in patients. The anxiolytic effects of SSRI are dependent on a chronic administration of the drug. Initially, SSRI can be anxiogenic in some patients. Preliminary results suggest that short-term treatment with hydrocortisone is anxiolytic. These results are significant because cortisol effect on anxiety is believed to be mediated via its action on the consolidation and retrieval of emotional memories. Our results suggest a direct effect on the expression of anxiety. One possibility is that cortisol potentiates the effect of the stress hormone corticotrophin releasing factor in limbic system structures such as the bed nucleus of the stria terminalis.[unreadable] [unreadable] Behavioral studies in patients: We showed that individuals with panic disorders have elevated contextual anxiety, but normal cued fear. Preliminary results from ongoing studies suggest a similar pattern of responses in PTSD but not in social phobia. These results suggest that patients with panic disorder and PTSD may share a common vulnerability to diffuse contextual threats. They also suggest that anxious patients are overly sensitive to unpredictable stressors. While patients with social anxiety disorder are not overly sensitive to non-specific stressors (e.g. mild shocks), they tend to form aversive Pavlovian associations with social stressors, suggesting that conditioning may be an etiological factor in this disorder.[unreadable] [unreadable] Neuroimaging: Using fMRI, we demonstrated that a different set of brain areas is activated by cue fear and contextual anxiety. In particular, context conditioning is associated with activation of a network encompassing the amygdala, hippocampus, parahihpocampal cortex, orbito frontal cortex, and subjenual anterior cingulate. These results are consistent with basic findings and rodents. Navigation in the Morris water maze was investigated with magnetoencephalography, with a special focus on the hippocampal and on parahippocampal theta oscillations. Two early peaks of left hippocampal and parahippocampal theta activity were observed during navigation to a hidden platform. Our results suggest that hippocampal and parahippocampal theta oscillations increased specifically under conditions in which spatial information is being encoded and/or retrieved rather than being elicited solely by virtual movements in general. There was also a linear relationship between hippocampal and parahippocampal theta responses and navigation performance on the vMWM, consistent with the interpretation that oscillatory activity is involved in spatial learning.